The germicidal properties of silver, even not known as such, have been utilized since the early Mediterranean cultures. It has been known since 1000 BC and possibly before that water kept in silver vessels and then exposed to light and filtered could be rendered potable. Other forms of silver have been used throughout centuries for various applications, such as coatings for prevention of beverages from spoilage or silver plates and foils in the surgical treatments of wounds and broken bones.
The lethal effects of metals towards bacteria and lower life forms were first scientifically described by von Nageli in the late nineteenth century, and this phenomenon has been defined as an “oligodynamic effect” (N. R. Thompson, Silver, in Comprehensive Inorganic Chemistry, Vol. III D, J. C. Bailer, H. J. Emeléus, R. Nyholm and A. F. Trutman-Dickenson, Editors, Pergamon Press, Oxford (1973)). The term oligodynamic effect is typically restricted to describing solutions in which the metal concentration is several orders of magnitude lower than that which would be lethal to higher organisms.
The investigation of the bacteriostatic properties of pure metals such as Fe, Mo, Cu, V, Sn, W, Au, Al, Ta, Nb, Ti, Zr, Ni, Co, Ag and Cr, has proved that Co was the only element which was inhibitory for the bacterial growth under anaerobic conditions (K. J. Bundy, M. F. Butler and R. F. Hochman, “An Investigation of the Bacteriostatic Properties of Pure Metals”, Journal of Biomedical Materials Research, Vol. 14 (1980) 653-663). Under aerobic conditions both Cu and Co consistently display inhibitory effects. Some antimicrobial effects have been seen for Ni, Fe and V. However, other metals such as Mo, W, Al, Nb, Zr, Cr and most importantly for the present invention Ag and Sn never showed any tendency to inhibit the growth of Streptococcus mutans. 
In the case of silver metal, it was in 1920, when Acél who was the first to attribute the antimicrobial properties of silver to the liberation of Ag+ ions from the material (D. Acél, “Über die oligodynamische Wirkung der Metalle”, Z. Biochem., 112 (1920) 23).
Gibbard reported in 1937 that pure metallic silver has no antimicrobial activity (J. Gibbard, “Public Health Aspects of the Treatment of Water and Beverages with Silver”, Journal of American Public Health, Vol. 27 (1937) 112-119). His experiments showed that if silver is cleaned mechanically with an abrasive cloth or paper it becomes inactive. Similarly, if molten silver is allowed to cool in a reduction atmosphere (e.g. hydrogen), no antimicrobial activity is found. When cooling of molten silver is carried out in air, and formation of surface oxide occurred, an antimicrobial activity may be observed. Similar results were found when silver metal was treated with nitric acid in an air atmosphere (dissolution and formation of an oxide layer). Based on Gibbard's results, pure silver was devoid of activity, but surface oxidized silver was active. Silver oxide, silver nitrate and silver chloride were always active. Also, Gibbard observed that the antimicrobial properties of silver and its compounds were reduced in the presence of proteins or glucose.
Djokić investigated the behavior of silver films, e.g. physical vapor deposited, electrodeposited, electroless deposited and metallurgical in physiological saline solutions (S. S. Djokić and R. E. Burrell, “Behavior of Silver in Physiological Solutions”, Journal of the Electrochemical Society, Vol. 145 (5) (1998) 1426-1430). Djokić found that an essential factor leading to an antimicrobial activity of metallic silver is a presence of Ag oxide(s) at the surface of this material. It was demonstrated that only silver films containing silver oxides (most likely Ag2O) showed an antimicrobial activity. The behavior was attributed to the dissolution of Ag2O from the “silver” material and formation of Ag+ or other complexed ions which become antimicrobially active. There was no evidence that pure metallic silver, no matter which way it was produced i.e., physical vapor deposited, electrodeposited or electroless deposited could be dissolved in physiological media, or that these materials would exhibit antimicrobial activity.
It should be noted that when the physical vapor deposition of silver was carried out in an atmosphere containing oxygen the resulted product, as found by the XRD analysis contained silver oxide. Consequently, these samples exhibited antimicrobial activity. Conversely, when the physical vapor deposition was carried out from an argon atmosphere (no presence of oxygen) pure metallic, nanocrystalline silver film was deposited as confirmed by the XRD analysis. However, these films did not dissolve in physiological saline solutions, nor they exhibited antimicrobial activity at all.
For an in depth understanding of structural properties of silver films produced by reactive sputtering, see Djokić et al. (S. S. Djokić, R. E. Burrell, N. Le and D. J. Field, “An Electrochemical Analysis of Thin Silver Produced by Reactive Sputtering”, Journal of the Electrochemical Society, Vol. 148 (3) (2001) C191-C196.). To prove the concept that only oxidized silver species are responsible for the antimicrobial activity, Djokić further oxidized pure metallic silver samples (i.e. those produced by the electrodeposition, electroless deposition, physical vapor deposition in an argon atmosphere or metallurgically). The oxidation of these samples was carried out electrochemically in 1 M KOH solutions, using a process very well established in the art. The electrochemically oxidized silver samples were tested for the antimicrobial activity against Pseudomonas Aeruginosa. Clear evidence was found that the electrochemically oxidized silver samples exhibited antimicrobial activity.
The above referenced work shows that only oxidized silver species, but not elemental silver will affect antimicrobial activity. The findings to date show that the “nanocrystalline” or “macrocrystalline” elemental silver does not have antimicrobial activity at all. Elemental silver, either nanocrystalline or “macrocrystalline” may exhibit some antimicrobial activity only if oxidized silver species are present at these surfaces or within the silver metal. Only the formation of silver oxide(s), carbonates or other silver salts (except silver sulfide, due to its extremely low solubility) at the surface or within the material, which may be influenced by an exposure of elemental silver to various bases, acids or due to atmospheric corrosion may lead to an antimicrobial activity of this material.
The use of silver on chronic wounds dates back in the 17th and 18th centuries. In the early 19th century, silver nitrate began to be used on burns and in opthalmology. Concentrations of the solution ranged from 0.20 to 2.5 wt. % with the weaker solutions being reserved for children. Silver has been found to be active against a wide range of bacterial, fungal and viral pathogens. Topical treatment of acute and chronic wounds is a preferred and selective approach to the prevention of infection and healing. In order to achieve these requirements products that are used in the prevention of infections must have certain physical and chemical properties.
When used for topical dressings, silver compounds must have relatively low solubility. This is usually achieved by choosing compounds with a relatively low solubility products (e.g. AgCl, Ag2SO4, Ag2CO3, Ag3PO4, Ag-oxides). Kinetics of dissolution of these compounds in neutral aqueous solutions is quite slow. This property is very convenient for two reasons. First, a sustained release of silver ions from the silver compounds is more likely to provide a prolonged antimicrobial activity. Second, low amounts of the silver ions released into wound exudates may not give rise to transient high tissue blood and urine levels, thus avoiding systemic toxicity. The choice of a particular silver compound will depend upon its reactivity with wound exudates. This reactivity should preferably be minimized in order to achieve the desired effect of the released silver ions (i.e., antimicrobial activity without systemic toxicity).
Besides silver nitrate, one of the most widely used topical antimicrobial materials is silver sulfadiazine (C. L. Fox, “Topical Therapy and the development of Silver Sulfadiazine”, Surgery, Gynecology & Obstetrics, 157 (1) (1983) 82-88). This compound is synthesized from silver nitrate and sodium sulfadiazine. Silver sulfadiazine has been used in treatments of burns, leg ulcers and also as a topical antimicrobial agent in the management of infected wounds.
Products such as silver protein (argyrols) or mild silver protein are mixtures of silver nitrate, sodium hydroxide and gelatin. These products are recommended for internal use and are promoted as essential mineral supplements. Although there is no theoretical or practical justification for their use, this class of compounds has been recommended for the treatment of diverse diseases such as cancer, diabetes, AIDS and herpes (M. C. Fung, D. L. Bowen, “Silver Products for Medical Indications: Risk—Benefit Assessment”, Clinical Toxicology, Vol. 34 (1) (1996) 119-126).
Silver-zinc-allantoinate has been formulated as a cream and represents a combination of silver, zinc and allantoin (an agent that stimulates debridement and tissue growth (H. W. Margaf, T. H. Covey, “A Trial of Silver-Zinc-Allantoinate in the Treatment of Leg Ulcers”, Arch. Surg., Vol. 112 (1977) 699-704). This composition exhibited promising effects in preliminary studies.
In the past few decades several topical dressings containing silver have been developed for wound care. Such materials include Arglaes™, Silverlon™, Acticoat™, Actisorb™, and Silver 220™.
Antimicrobial coatings and methods of forming same are the subject of U.S. Pat. No. 5,681,575 (Burrell et al) and U.S. Pat. No. 6,238,686 (Burrell et al). The coatings are formed by the physical vapor deposition of biocompatible metal and the preferred biocompatible metal is silver.
Burrell et al teach that atomic disorder may be created in metal powders or foils by cold working and in metal coatings by depositing by vapor deposition at low substrate temperatures and that such metal coatings constitute a matrix containing atoms or molecules of a different material. The presence of different atoms or molecules results in atomic disorder in the metal matrix, for instance due to different sized atoms. The different atoms or molecules may be one or more second metals, metal alloys or metal compounds which are co- or sequentially deposited with the first metal or metals to be released. Alternatively, the different atoms or molecules may be adsorbed or trapped from the working gas atmosphere during reactive vapor deposition.
In U.S. Pat. No. 6,238,686 Burrell et al claim a modified material comprising one or more metals in a form characterized by sufficient atomic disorder such that the material, in contact with a solvent for the material, releases atoms, ions, molecules or clusters containing at least one metal at an enhanced rate relative to its normal ordered crystalline structure. In U.S. Pat. No. 5,681,575 Burrell et al claim a medical device which includes a coating of one or more anti-microbial metals having a “sufficient atomic disorder”.
It is unclear from either U.S. Pat. Nos. 5,681,575 or 6,238,686 what would constitute a material characterized by “sufficient atomic disorder”. In nature, most materials would exhibit sufficient atomic disorder if the true atomic disorder described (by drawings or mapping) in ordinary Chemistry or Physics handbooks were insufficiently ordered (with a regular geometric structure or like).
In any event, the teachings of Burrell et al appear to connect “atomic disorder” with an “enhanced rate” of release of “atoms, ions, molecules or clusters”. If the term “release” further relates to a dissolution (as defined in textbooks of General Chemistry and Physics), then this dissolution should lead to the liberation of ions or molecules in solvent. When released in the solvent, these ions or molecules are usually solvated i.e. surrounded by the molecules of the solvent. It is very unlikely that atoms of a metal will be released into a solution comprising of water such as in the wound environment. If released into solution in its elemental state, metals would rather represent a relatively larger particles comprising of more than one or a few atoms.
As a result, the term “atom” as used in Burrell et al is not exactly descriptive. It is not known yet scientifically whether atoms of metals can be released into aqueous solutions at pH close to neutral (e.g., pH range 6 to 8), except in the case of colloidal solutions which are usually prepared by adequate chemical reactions in-situ.
U.S. Pat. No. 6,087,549 (Flick) discloses a multilayer laminate wound dressing comprising a plurality of layers of a fibrous material, with each layer comprising a unique ratio of metalized fibers to nonmetalized fibers. In a preferred embodiment the wound dressing consists of three layers and the metal is silver. The wound contact layer has the highest ratio of metalized fibers to nonmetalized fibers, the intermediate layer has a lower ratio of metalized fibers to nonmetalized fibers, and the outer layer has the lowest ratio of metalized fibers to nonmetalized fibers. The wound dressing described by Flick is commercially available under the trade-mark Silverlon™.
U.S. Pat. No. 5,211,855 (Antelman), U.S. Pat. No. 5,676,977 (Antelman) and U.S. Pat. No. 6,436,420 (Antelman) teach that tetrasilver tetroxide (Ag4O4) containing two monovalent and two trivalent silver ions exhibits bactericidal, fungicidal and algicidal properties. As a result, “tetrasilver tetroxide” is suggested for use for water treatment in U.S. Pat. No. 5,211,855 and for use in destroying the AIDS virus in U.S. Pat. No. 5,676,977.
In U.S. Pat. No. 6,436,420, Antelman describes a method of deposition or interstitial precipitation of tetrasilver tetroxide (Ag4O4) crystals within the interstices of fibers, yarns and/or fabrics forming such articles in order to produce fibrous textile articles possessing enhanced antimicrobial properties. The interstitial precipitation of Ag4O4 is achieved by immersion of the article to be treated (e.g., fiber, yarn or fabric) in an aqueous solution containing a water soluble silver salt, most preferably silver nitrate. After uniformly wetting the article, the article is removed into a second heated aqueous solution (having a temperature of at least 85 degrees Celsius or more preferably at least 90 degrees Celsius) containing strong alkali (most preferably NaOH) and a water soluble oxidizing agent (most preferably potassium persulfate) for 30 seconds to 5 minutes to facilitate the precipitation of tetrasilver tetroxide.
After the reaction is completed, the article is removed and washed. The article treated in this way is described as exhibiting outstanding antimicrobial resistance towards pathogens such as bacteria, viruses, yeast and algae. The article is also described as being resistant to ultraviolet light and as maintaining its antimicrobial properties after a number of launderings.